⁠STATISTICAL ASSOCIATION BETWEEN NEUROTRANSMITTER-RELATED GENE EXPRESSION AND REGIONAL BRAIN VULNERABILITY

Abstract

Neurotransmitter-related molecular organization contributes to structural heterogeneity across the human brain, but its spatial relationship with regional brain vulnerability remains insufficiently quantified. Limited integration of neurotransmitter-related gene expression with regional structural measures restricts understanding of molecular–anatomical relationships. This work investigates the statistical association between glutamatergic and gamma-aminobutyric acid (GABA) –related gene expression and regional brain structural measures. Post-mortem transcriptomic data from the Allen Human Brain Atlas (AHBA), comprising 3,702 tissue samples from six adult human donors and more than 58,000 probes, were aggregated into 68 matched anatomical regions. Predefined glutamatergic and GABAergic gene sets were used to derive regional expression scores and align them with cortical thickness and subcortical matter volume. Pearson correlation, partial correlation, Benjamini–Hochberg false-discovery-rate correction, partial least squares (PLS) regression, Moran’s I, and spatial autoregressive (SAR) modeling were applied. Glutamatergic expression showed a strong inverse association with Cortical thickness (r = −0.61, p < 0.001), remaining significant after covariate adjustment (r = −0.56, p < 0.001) and spatial adjustment (β = −0.49, p = 0.002). It was also inversely associated with subcortical matter volume (r = −0.52, p < 0.001). GABAergic expression showed inverse associations with cortical thickness (r = −0.43, p < 0.001) and subcortical matter volume (r = −0.37, p = 0.002. Overall, neurotransmitter-related molecular organization was significantly associated with regional brain structural variation, with glutamatergic expression showing the strongest association. These findings represent statistical relationships and do not establish causality.